Most cases of genital herpes are due to herpes simplex virus (HSV)-2. The rate of HSV-2 infections increased by 30% from 1988 to 1994. In addition to genital herpes, transmission of HSV-2 to neonates causes severe life-threatening infections. HSV-2 infection also increases the risk of transmission and infection with HIV. Thus a vaccine for HSV-2 would not only reduce the rate of genital herpes, but also might reduce spread of HIV. Several HSV-2 vaccines have been tested in humans for prevention or reduction of genital herpes disease. A vaccine containing a single viral protein (HSV-2 glycoprotein D) recently showed no evidence for protection against genital herpes in a large international, phase three, randomized controlled trial in HSV-2 seronegative women. We postulate that the limited efficacy of the HSV-2 glycoprotein D vaccine is likely due to inadequate induction of broadly neutralizing antibody and cellular immune responses. We cloned the entire HSV-2 genome into a plasmid containing a bacterial artificial chromosome BAC). We showed that virus derived from the HSV-2 BAC replicated in cell culture at the same rate as wild-type virus and that mice infected with virus derived from the HSV-2 BAC developed disease as well as latent HSV-2 infection at a similar rate as animals infected with wild-type virus. We have engineered mutations in the HSV-2 BAC and have obtained HSV-2 with mutations in the viral glycoprotein D (gD) that are critical for the interaction of gD with one of its receptors, nectin-1, but not with another receptor, HVEM. Since HVEM is expressed on epithelial cells and lymphocytes, while nectin-1 is expressed on neurons and epithelial cells, the HSV-2 gD mutant would be predicted to be impaired for infecting neurons, but not epithelial cells and therefore might induce a potent immune response, but not cause neurologic disease in animals.